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TCP Informational Interview Series: Dr. Reynold Spector

August 10, 2017

ASPET'17_014-Spector-Award-crop-(2)Reynold Spector, M.D., has served as a full Professor of Medicine at University of Iowa and the Robert Wood Johnson Medical School in New Jersey. Dr. Spector also served as a visiting Professor of Biochemistry in Arthur Kornberg’s Department of Biochemistry during his sabbatical at Stanford University. After his retirement in 1999, he has also served as a visiting Professor of Medicine in the Harvard-MIT program in the Health Sciences. Dr. Spector has also held numerous leadership positions in the pharmaceutical industry including Executive Vice President of Clinical Sciences at Merck Research Laboratories, where he was instrumental in overseeing the development of multiple valuable drugs and vaccines now used by tens of millions of persons worldwide. Dr. Spector received his medical degree from Yale University and his bachelor’s degree from Harvard College, and has authored and co-authored more than 160 peer-reviewed articles, books, and book chapters.

Why did you choose a career in biomedical sciences and what specifically motivated you for a career in pharmaceutical industry?

My career choices evolved over time. My father was a pharmacist who taught me about chemistry, which as a child and even today, I believe borders on magic. Chemistry is clearly the basis for pharmacology. Moreover, my father when I was a child (I am told) wished me to be a physician. So it was almost inevitable that at Harvard College I majored in chemistry and physics although I had a strong interest in philosophy. In chemistry I did extremely well – almost as if I had known it in a former life. After college I went to Yale Medical School, did my internship and residency in internal-medicine at the Brigham in Boston and without a fellowship became an instructor in medicine at Harvard. My training at these institutions (wherein I met many role models including several Nobelists) was difficult but superb.

When I joined the Harvard faculty, my research interests were in questions about how drugs, vitamins and hormones crossed the blood-brain and blood-cerebrospinal fluid (CSF) barrier, phenomenologically non-linear pharmacokinetics. I was generously supported by the NIH and we made a series of discoveries especially dealing with vitamin transport and homeostasis in the brain. However, I did spend about 20% of my time attending on the general medicine service and became associate director of the outpatient medical clinic at the Brigham. Part of this clinical work involved studies of medication compliance which we published. In 1975, the Chief of Medicine at the Brigham suggested I start a Clinical Pharmacology group which I did, initially with two fellows.

In 1978, I was offered a full professorship of medicine and pharmacology at the University of Iowa. My nine years there were very productive in both my basic and clinical research. My clinical roles included being Head of Clinical Pharmacology and General Medicine, and later Director of the NIH funded Iowa Clinical Research Center One of our major clinical achievements was the discovery and description of gastrointestinal dialysis with multiple doses of oral activated charcoal in the treatment of poisoning, published initially in the New England Journal of Medicine in 1982.

In education, I believed that our medical school students were deficient in knowledge of the use of drugs. So after substantial controversy, I persuaded the medical school faculty at the University of Iowa to include a mandatory course in Clinical Pharmacology in the otherwise elective fourth year. My junior colleagues and I wrote a very successful textbook for that course (The Scientific Basis of Clinical Pharmacology; Little-Brown 1985).

In 1987, Merck recruited me to become head of clinical pharmacology. Over a period of several years, I assumed increasing responsibility culminating in my promotion to Executive Vice President in charge of drug development. Please note in the rest of my answers I will be talking about development, not discovery which is the second major part of research in the innovative prescription drug industry. Discovery involves the finding of compounds for potential development into drugs or vaccines.  From 1995 to 1999, we developed, registered and sold ten new drugs, including losartan, alendronate, montelukast, and simvastatin, and several vaccines. We proved the value of these drugs in large clinical outcome trials. For example, simvastatin and losartan save lives; alendronate reduces fractures and so forth. These drugs – the first in their class sold well because the prescribers and public knew they were effective clinically. They excelled in the ultimate test, the “test of time.”

My motivation to move from academia to industry was manifold. One of the major challenges for me was the question: Could I transform what I taught in the classroom and on the wards into the development of actual products? But to do this, i.e., to lead and manage a huge development organization, I needed to learn about management and leadership.  I knew something about these topics because for two years (1968-1970) I served in the US Army (Major, Medical Corps) and carefully studied the US Army organization. However, when I moved to Merck I bought several management textbooks and quickly mastered them. I also thought deeply about leadership and concluded one of the essential keys to success was the recruitment of top-notch personnel. Since we had a very large budget and were on a “roll,” I was able to recruit extremely talented well trained physicians and Ph. D.’s. Within the company, we had a mini-university where, when necessary, we taught our recruits critical knowledge like pharmacokinetics and statistics. It was extremely rewarding to work with such bright energetic young physicians and Ph. D. scientists. I was able to inculcate the notion that our job was not only to do and publish superb basic/clinical science but the endpoint, unlike in academia was not publications (new knowledge), but products that had real value. The principles that I wrote about in my textbook were just as true in industry as in academia.

Did you encounter any specific challenges while transitioning and/or working in academia versus the pharmaceutical industry?

As noted above, several of the biggest challenges in developing products in industry, unlike academia, are the regulatory hurdles that are required to register a drug for sale. In fact, in the past, these regulatory requirements were reasonable but involved an immense amount of work by many groups. Second, the clinical pharmacology groups needed to team up with multiple other groups to carry out their work effectively e.g., statisticians, animal safety assessment scientists, laboratory personal who measured drug concentrations or biochemical variables, in project teams. To do this effectively you must “leave your ego at the door.” There is no room for prima donnas. Third, clinical pharmacologists needed to learn how to present data in defense of their work – e.g., during FDA advisory committee meetings. This often was and is a huge challenge even when the data are correct and clear.

What things did you like most about your job in various capacities over the years?

At Merck, every two weeks we alternatively had a meeting of the senior developmental leaders in New Jersey or Pennsylvania to review the project teams plans/proposals from basic medical plans (phase I/ II programs) to the large clinical trials (phase III/IV). I insisted that any project team leader who wanted review and approval must send out their documents three days before the meeting. I received these paper documents before each meeting (as did all the senior personal) - about a one-foot stack to review. So before the meeting I knew the content and made certain the project team presenters presented expeditiously leaving time for questions.  Often after extensive discussion, the decision came down to a judgement call by me – the Chairman. Everyone looked at me for the decision, often about studies that would cost tens of millions of dollars. These go/no go decisions were difficult. In retrospect, since we ended up with many good products, the correct decisions look easy now but at the time – some were large gambles. Of course, in the background always was the concern that we would place on the market a drug that millions of patients would consume; we better be absolutely certain the drug was safe and effective. There was no room for a mistake. Fortunately the FDA approved all our submissions for drugs and vaccines during my tenure. However, in several cases post-marketing toxicities appeared. One example was the reflux and pill esophagitis that occurred rarely with alendronate. When we became aware of this we published (with the Mayo Clinic) the nature of the toxicity and how to avoid it in the New England Journal of Medicine. Some of the Merck marketing folks were fearful we would “kill” the drug but in fact this brutal honesty did not; and sales continued to rise because if taken properly alendronate is safe and effective in preventing fracturing. Two of my last projects were the herpes zoster and papilloma virus vaccine that were registered after I retired in 1999.  I recruited several absolutely brilliant medical scientists to develop these vaccines. As is now well known the papilloma virus vaccine prevents cancer of the cervix and other rarer cancers. I was also pleased to help in several key (but controversial at the time) decisions in these programs.

At the end of the day, “the proof is in the pudding.” I do not think there is any more intellectually and emotionally rewarding experience than developing a drug like simvastatin or vaccine like the papilloma virus vaccine. If I had a choice between a Nobel Prize and the development of life saving drugs like simvastatin or vaccines like the papilloma virus vaccine, I would choose the latter.

What were some of the most challenging aspects in your job? And what were the duties in your job that were essential but least enjoyable?

The challenges I alluded to above. Perhaps the biggest challenge at Merck for me was the never-ending workload. This dwarfed the workload in academia which was substantial.  Since we at Merck were a worldwide operation and I was also overseeing the Merck Medical Departments from China all the way around to Russia, my job was a 24/7 operation. The amount of paper work alone was immense. I tried as much as possible to leave work at 5:30 pm – have supper with my wife and children, take a ten-minute nap and then work on my paper work from 7 pm to about 10 pm. The secret was to move your inbox documents into your outbox the next morning. You could not fall behind.

A key component of the job was recruiting. My wife and I worked as a team on many occasions on this. One example was a young physician at the Mass. General that I felt we must have. I told her I would not accept a “no”. We finally succeeded and she became a “star.” Another fellow became president of an ivy-league university. Many others also became leaders in the industry or related fields.

What are some key strategies/skills that helped you succeed in your career?

The key to success beside knowledge and reasonable management and leadership skills was preparation. Before meetings, I generally knew what I wanted. Occasionally, I was persuaded at the meeting I was wrong and happily yielded. Also, by recruiting really intelligent personal, I allowed them on occasion to take risks that I thought were very difficult. Several times I almost collapsed to hear of their successes. Of course, knowledge of the principles and practices of clinical pharmacology, statistics, logic, chemistry, physiology and pathophysiology are prerequisites – it goes without saying. Finally I demanded hypothesis-oriented research from the project teams. No fishing expeditions were allowed and this coupled with mandatory prospective data analysis plans was just what the FDA and other regulators wanted.

Looking back over the years of experience in your field, do you think you would have done anything differently?

In retrospect, I don’t think we made any major errors. The products we developed were widely accepted and used. Now they are inexpensive and generic. Every one of our submissions was approved by the FDA and European regulatory agencies.  My only regret was our utter failure in making cancer, neurological and psychiatric treatment drugs. However, before I joined Merck, Maurice Hilleman and Roy Vagelos at Merck made the hepatitis B vaccine and we developed the papilloma virus vaccine. These are both cancer preventives; liver cancer and cervical cancer respectively. Prevention is obviously much better than treatment and this approach will be the key I believe to future progress.

What are some major developments that you see in the field of Immunopharmacology and Drug Development over the next decade? What do you see as the best opportunities for young people entering this field?

It is extremely difficult to predict. I believe so far immune-pharmacological drugs have a mixed legacy. Some hyped drugs like bevacizumab for cancer have had no real impact on (median) survival although very expensive and a “big seller.” On the other hand the antibody Prolia in the treatment of osteoporosis and the prevention of fracturing is an excellent treatment/preventive, requiring only one subcutaneous injection every six months. I currently have doubts about the effectiveness of immunotherapy against the common cancers in terms of prolonging survival significantly (years) or cures. But time will tell, not hype and hope.

For young people entering pharmacology/clinical pharmacology, this is potentially the golden age. There is an explosion of knowledge in biology which grows more complex daily. This opens opportunities for new targets and new drugs. One formidable problem is that our young M.D.’s and Ph. D.s have to learn how to continuously upgrade their knowledge base – a very difficult task with the rapid expansion of knowledge. Who knew just 2 years ago that circulomes (circular human viruses) would appear “out of nowhere” and become a major issue in cancer-causation.

Pharmacologists/clinical pharmacologists need expertise and familiarity with many fields to be “accomplished.” However, the rewards for success can be staggering. Diagnosis these days is relatively straightforward. Prevention and treatment in many cases are the challenge. At present, there is no good therapy for many cancers, Alzheimer’s, serious psychiatric disorders, and osteoarthritis; the list of untreatable disorders is long. We need young people with novel ideas and new approaches to make further progress.

Do you have any specific career advice for graduate students who are about to start their biomedical sciences career?

For Ph. D. graduate students, I urge them to learn not only the principles of pharmacology/clinical pharmacology but also related fields like medicinal chemistry, molecular biology, crystallography, statistics, logic, toxicology, physiology, pathophysiology and anatomy.  A good pharmacologist (basic and/or clinical) must have very broad knowledge – including regulatory requirements for drugs.

Do you have any specific career advice for graduates looking for jobs? How can young scientists make themselves competitive for a variety of career paths?

Physician and Ph.D. pharmacologists looking for jobs require integrity, good training and drive as noted above.  Productivity in academia involves generating new knowledge and teaching. In the innovative pharmaceutical industry, the focus generally is on patentable products. I have always believed and still do in the value of truth, truthfulness and transparency as summarized in the Yale motto “Lux et Veritas.” I also believe in hypothesis-oriented research; not “fishing” expeditions. Thus, even in animal research, one should (as much as possible) do blinded, randomized studies with adequate numbers to avoid bias. There are too many non-reproducible studies reported. Young scientists will often be asked about their beliefs and the answers should be precise and clear. To paraphrase, George Merck had it right when he said that pharmaceutical research physicians and Ph.D.’s should make good products (the key) and marketing and sales will follow as night follows day

What personal qualities are important for someone who wishes to follow a career trajectory similar to yours?

I believe, as noted above, integrity, knowledge, flexibility, preparation, drive to succeed and willingness to learn continuously are the keys. Hard work as Edison maintained is crucial. It is very difficult to find, develop and register new drugs and vaccines that “make a difference” but we know how: The principles of the scientific method and the selection of appropriate “targets” are “tried and true.” As an example, John Stewart Mill’s fifth and most powerful Method of Concomitant Variation – known in pharmacology as “dose-response” curves remains true and crucially useful. Once an FDA evaluator tried to explain (at a FDA consultants meeting), that we were not using Mill’s methods properly. I pointed out to this pompous reviewer that on slide 27 was a clear dose-response curve with very small error bars, Mill’s fifth method. The reviewer promptly sat down.

In your experience at a major pharmaceutical company, such as Merck, do the companies look for a specific personality fit in addition to qualifications?

Recruiting is very variable but I would say good companies seek the qualities noted in the answers to the previous questions.

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